In the past decade, directed C—H activations have been extended to a wide range of synthetically useful substrates and transformations.1 Nevertheless, the covalent installation and removal of directing groups often poses a major obstacle for their synthetic applications. In addition to adding two steps to the synthetic sequence, the reaction conditions for these steps are sometimes incompatible with labile functionalities on advanced synthetic intermediates.
Thus, developing catalytic directing groups that can transiently bond to the substrate for C—H activation and subsequently dissociate reversibly is highly desirable. This strategy has been successfully applied in a number of Rh(I)-catalyzed C(sp2)-H activations.2 Recently, our group discovered that simple amino acids can serve as an effective transient directing group for Pd(II)-catalyzed C(sp3)-H functionalization of aldehydes and ketones via a reversible imine linkage, thus demonstrating the feasibility of using transient directing groups for Pd(II) catalysts, although the loading of directing groups is still high (40%).3 Notably, the bicientate coordination system provided by the imine moiety and the weakly coordinating carboxylic acid points to a new direction for our long search of transient directing groups that assist the activation of C(sp3)-H bonds (Scheme 1(2)).
Following the success of identifying a transient directing group for ketones, we wondered whether similar approach could be applied for the activation of free amines. Amines are ubiquitous structural motifs in compounds with pharmaceutical, agrochemical and agricultural importance.4 While site-selective C—H functionalization of free aliphatic amine is highly desirable as it enables rapid late-stage modifications and derivations, this process is traditionally difficult due to the formation of the unreactive Pd(RNH2)2X2 complexes,5 as well as the vulnerability of amines towards a-oxidation and electrophiles.6 Nevertheless, numerous methods have been developed for the C—H functionalization of amines with various protecting groups.7-9 An interesting b-C—H functionalization of free secondary amines (R2NH) has also been reported, although bulky a-quaternary center is required for this reaction.10 